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A mutant connexin50 with enhanced hemichannel function leads to cell death.

Abstract：

PURPOSE:To determine the consequences of expression of a novel connexin50 (CX50) mutant identified in a child with congenital total cataracts. METHODS:The GJA8 gene was directly sequenced. Formation of functional channels was assessed by the two-microelectrode voltage-clamp METHOD:Connexin protein levels and distribution were assessed by immunoblot analysis and immunofluorescence. The proportion of apoptotic cells was determined by flow cytometry. RESULTS:Direct sequencing of the GJA8 gene identified a 137 G>T transition that resulted in the replacement of glycine by valine at position 46 of the coding region of CX50 (CX50G46V). Both CX50 and CX50G46V induced gap junctional currents in pairs of Xenopus oocytes. In single Xenopus oocytes, CX50G46V induced connexin hemichannel currents that were activated by removal of external calcium; their magnitudes were much higher than those in oocytes injected with similar amounts of CX50 cRNA. When expressed in HeLa cells under the control of an inducible promoter, both CX50 and CX50G46V formed gap junctional plaques. Induction of CX50G46V expression led to a decrease in the number of cells and an increase in the proportion of apoptotic cells. CX50G46V-induced cell death was prevented by high concentrations of extracellular calcium ions. CONCLUSIONS:Unlike previously characterized CX50 mutants that exhibit impaired trafficking and/or lack of function, CX50G46V traffics properly to the plasma membrane and forms functional hemichannels and gap junction channels; however, it causes cell death even when expressed at minute levels. The biochemical results indirectly suggest a potential novel mechanism by which connexin mutants could lead to cataracts: cytotoxicity due to enhanced hemichannel function.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Minogue PJ,Tong JJ,Arora A,Russell-Eggitt I,Hunt DM,Moore AT,Ebihara L,Beyer EC,Berthoud VM

doi

10.1167/iovs.09-3759

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

5837-45

issue

12

eissn

0146-0404

issn

1552-5783

pii

iovs.09-3759

journal_volume

50

pub_type

杂志文章

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